In recent years, an attention has been invited to relation between cell adhesion proteins and the carbohydrate chain. Selectins including ELAM-1, GMP-140 and LECAM-1 are a cell adhesion protein which has a lectin-like domain, an EGF-like domain and a complement binding protein-like domain successively from the N terminus and a receptor of general class. These cell surface receptors are expressed on a variety of cells. ELAM-1 is an adhesion protein which is expressed on vascular endothelium and is bound to the carbohydrate chain ligand on the side of leukocyte. ELAM-1 is thought to be temporarily expressed on the blood vessel at the site of inflammation when stimulated by an inflammatory cytokines of IL-1 or the like, which plays a role of collecting the leukocytes and helping their migration to the site of lesion. Further, it was recently clarified that the ligand carbohydrate chain was expressed on cancer cells, and ELAM-1 is thought to be involved in hematogenous metastasis of cancers (Takada A. et al. Cancer Res. 53: 354-361, 1993).
Now, various approaches have been suggested to prevent inflammation and cancer metastasis by blocking the action of selectins and thus inhibiting cellular adhesion.
WO 91/19501 (published on Dec. 6, 1991) discloses a method for reducing or treating inflammation and other pathological symptoms which are mediated by intercellular adhesion, by using a compound having an oligosaccharide moiety containing fucose and sialic acid, as a ligand binding to selectin.
WO 91/19502 (published on Dec. 26, 1991) discloses compounds having the selectin-binding moiety of the general formula, R.sub.1 -Gal.beta.1,4(Fuc.alpha.1,3)GlcNAc-(R.sub.2).sub.a, wherein R.sub.1 is an oligosaccharide or R.sub.3 -R.sub.4 --C(CO.sub.2 H)--, R.sub.3 and R.sub.4 are the same or different and each is H, C.sub.1 -C.sub.8 alkyl, hydroxyl C.sub.1 -C.sub.8 alkyl, aryl C.sub.1 -C.sub.8 alkyl or alkoxy C.sub.1 -C.sub.8 alkyl; and R.sub.2 is .beta.1, 3Gal, .alpha.1, 2Man or .alpha.1, 6GalNac; and a is 0 or 1.
WO 92/02527 (published on Feb. 20, 1992) discloses the compounds, as a ligand binding to ELAM-1, of the general formula ##STR3## In the formula, each of the saccharide rings shown is connected at its 1-position to the next saccharide ring at its 3-position or 4-position and wherein the variables are defined as follows:
At least one of A and B is ##STR4## and the other is H, wherein R.sup.4 is --(CHOH).sub.3 H, H, alkyl containing 1 to 6 carbons, CHO, or perfluoroalkyl containing 1 to 6 carbons;
R.sup.5 is selected from the group consisting of H, alkyl containing 1 to 6 carbons, COCH.sub.3, COCH.sub.2 OH, COCF.sub.3 ; and PA1 R.sup.6 is selected from the group consisting of H, and an alkyl containing 1 to 6 carbons; PA1 each D is independently H, a galactosyl or fucosyl wherein at least one D is .alpha.-fucosyl connected to the 3-position or 4-position of the sugar to which it is bound; PA1 each R.sup.3 is independently OH or NAc; PA1 n is an integer of from 0 to 10 with the proviso that if n is 0 and F is H, R.sup.3 is OH; PA1 F is H, a ceramide residue, or comprises a linking group or a solid support or a pharmaceutically active drug; PA1 X is selected from the group consisting of O, S and NR.sup.6 and in the saccharide at the reducing terminus, X may also represent the corresponding dicarbinol at C-1 and C-5. PA1 Ac: Acetyl PA1 Me: Methyl PA1 Et: Ethyl PA1 Ph: Phenyl PA1 Bn: Benzyl PA1 MPM: Methoxybenzyl PA1 Bz: Benzoyl PA1 SE: 2-Trimethylsilylethyl PA1 Tf: Trifluoromethanesulfonyl PA1 CPA: 2-chlorolactic acid PA1 DBU: 1,8-Diazabicyclo-[5.4.0]-7-undecene PA1 DMAP: Dimethylaminopyridine PA1 DMF: Dimethylformamide PA1 DMP: 1,3-Dimethoxypropane PA1 MS: Molecular sieves PA1 NIS N-Iodosuccinimide PA1 PTS: p-Toluenesulfonic acid PA1 TBAB: Tetrabutylammonium bromide PA1 TFA: Trifluoroacetic acid PA1 WSC 1-Ethyl-3-(dimethylaminopropyl)carbodiimide, hydrochloride
Recently, ligand carbohydrate chains having different properties were discovered from the difference in the constituent carbohydrate residues other than sialic acid and Le.sup.x hapten portions in sialyl Le.sup.x carbohydrate chain, that is, variations in the O-glycoside bonded carbohydrate chain and the N-glycoside bonded carbohydrate chain of the glycolipids and glycoproteins. Thus, it has been becoming known that a series of these; sialyl Le.sup.x variants are also of a delicately different physiological significance.
With the elucidation of the ligand-receptor interaction it will be possible to develop compounds which inhibit selectin-mediated cellular adhesion which is useful in therapeutic regimens.